Compounds having growth hormone releasing activity

ABSTRACT

Compounds that promote growth hormone releasing activity are disclosed. These compounds have the formula:
 
A 1 -A 2 -X; A 1′ -X′; or A 1′ -Y
 
     These compounds can be present in a pharmaceutical composition. The compounds can be used with a second compound that acts as an agonist at the growth hormone releasing hormone receptor or which inhibits the effects of somatostatin. These compounds can be used for a variety of uses such as treating hypothalamic pituitary dwarfism, osteoporosis, burns, or promoting wound healing.

This application is a divisional of copending application Ser. No. 09/370,111, filed Aug. 6, 1999, which is hereby incorporated by reference, which claims benefit of provisional applications 60/096,795, filed Aug. 14, 1998 and 60/129,806, filed Apr. 16, 1999.

FIELD OF THE INVENTION

This invention relates to novel compounds that promote the release of growth hormones when introduced to animals, preferably humans, and methods of use thereof.

BACKGROUND OF THE INVENTION

The elevation of growth hormone (GH) levels in animals, e.g., mammals including humans, upon administration of GH-releasing compounds can lead to enhanced body weight and to enhanced milk production if sufficiently elevated GH levels occur upon administration. Further, it is known that the elevation of growth hormone levels in mammals and humans can be accomplished by application of known growth hormone releasing agents, such as the naturally occurring growth hormone releasing hormones.

The elevation of growth hormone levels in mammals can also be accomplished by application of growth hormone releasing peptides (GHRPs), some of which have been previously described, for example, in U.S. Pat. Nos. 4,223,019; 4,223,020; 4,223,021; 4,224,316; 4,226,857; 4,228,155; 4,228,156; 4,228,157; 4,228,158; 4,410,512; 4,410,513.

Antibodies to the endogenous growth hormone release inhibitor, somatostatin (SRIF) have also been used to cause elevated GH levels. In this latter example, growth hormone levels are elevated by removing the endogenous GH-release inhibitor (SRIF) before it reaches the pituitary, where it inhibits the release of GH.

These methods for promoting the elevation of growth hormone levels frequently involve materials which are expensive to synthesize and/or difficult to isolate in sufficient purity for administration to a target animal. Low molecular weight, relatively simple and inexpensive compounds that have the ability to promote the release of growth hormone would be desirable in that they could be readily and inexpensively prepared, easily modified chemically and/or physically, as well as easily purified and formulated, and designed to have improved transport properties.

GH and/or GHRPs have been administered to stimulate growth hormone production and/or release, for example, to stimulate growth, enhance milk production, enhance body weight, increase rate of protein synthesis, reduce rate of carbohydrate utilization, increase mobilization of pre-fatty acids. Although the use of many of these compounds such as a series of short peptides (e.g., U.S. Pat. Nos. 5,663,146 and 5,486,505) have been important steps in the design and delivery of compounds having GH and/or GHRP properties, improvements can still be made. For example, improvements can be made in the areas of oral bioavailability, serum retention time, etc.

Non-peptidal or hybrid-peptidal secretagogues have also been described. See U.S. Pat. Nos. 5,494,919; 5,492,920; 5,492,916; 5,622,973; WO95/13069, WO96/15148; WO96/35713; WO97/22367; WO97/00894; WO97/07117; and WO97/11697. Despite the general descriptions of such compounds, it is not possible to make broad generalizations about which particular compounds are favorable. Although some secretagogues, which can promote the release and elevation of growth hormone levels in the blood, have been described, corresponding data on the biological activity has often been lacking. Moreover, even in terms of tripeptides with or without C-terminal modifications, the data suggests that it has heretofore been impossible to make the broad sweeping generalization made in those publications about what would or would not be a favorable amino acid combination at the three positions of a tripeptide holding the C-terminal constant or holding the peptidal portion constant while making changes, or changing the chemical moieties added. Changes in any of the constituents can have great effects on activity. It is submitted that these references do not lead to general teachings of biological efficacy.

In order to maximize the ability to select and tailor a compound, it would be desirable to have a class of compounds that generally provide good growth hormone releasing effects and have at least one other desirable biological activity such as better bioavailability, absorption, metabolism, pharmacokinetics, excretions, etc. It would also be desirable to have compounds which can promote the release and elevation of growth hormone levels in the blood of animals, particularly in humans, to be able to use such compounds to promote the release and/or elevation of growth hormone levels in the blood of animals and humans, and to provide methods for promoting the release and/or elevation of growth hormone levels in the blood of animals using such compounds.

The aforementioned discussion illustrates that a broad chemical diversity of synthetic GHRPs ranging from peptides to partial peptides to non-peptides. Overall, the peptides and partial peptides have been the most effective in promoting elevated growth hormone levels. For example, partial peptides consisting of natural and unnatural amino acids of different chain lengths and C-terminal amide groups or a substituted amide with various organic chemical groups. Results published as early as 1982 stated that certain GHRPs with only 3-7 amino acids released GH and that having a D-amino acid at certain positions was useful. From 1982 to the present, GHRPs with more potent GH releasing activity have been developed. This research taught that certain amino acid positions could have certain substitutions but not others, and that one amino acid residue could affect what other substitutions could be made.

Until compounds having the optimum physical-chemical properties and physiological-biological actions and effects are discovered for various diagnostic and therapeutic uses in humans, it is important to discover a general chemical approach that will result in new types of GHRPs. Such a broader GHRP chemical base will make it possible to better implement and refine the GHRP approach.

Properties of GHRPs that are important include that they are effective when administered orally. In addition, the compound should augment the normal pulsatile physiological secretion of GH. In some subjects with decreased GH secretion, GH can be replaced in a physiological way. Physiological replacement of a hormonal deficiency improves health while minimizing the potential adverse action of the hormone. This is especially important in treating older men and women, as they may be particularly susceptible to the adverse effects of over-treatment with GH. Already, chronic administration of GHRPs to animals and humans has produced anabolic effects. Body weight gain has been increased in rats, milk production has been increased in cows. Additionally, when a compound such as DAla-DβNal-Ala-Trp-DPhe-Lys-NH₂ (GHRP-2) was administered to short-statured children with various degrees of GH deficiency 2-3 times per day over a 2 year period, the rate of height velocity has been accelerated in those children.

In principle, the anabolic biological effects of GHRPs emphasize the potential clinical value of the GHRP approach. The finding that GHRP-2 is less effective on height velocity than usually obtained with chronic recombinant human growth hormone (rhGH) administration, underscores the desirability for improving the GHRP approach. This includes further optimization and extension of the range of the GHRP chemistry in order to produce more effective biological actions.

In looking at these compounds, one looks at a varied series of biological effects such as the duration of action of GHRP. Other parameters that may substantially be affected by the chemistry of the GHRP include desensitization of the GHRP GH response, actions on the hypothalamus, effects on SRIF release and action, effects on ACTH and PRL release as well as possible effects on putative subclasses of GHRP receptors. All of these actions are directly and/or indirectly dependent on the GHRP chemistry, pattern and efficiency of oral absorption as well as the metabolism and secretion of the particular GHRP.

SUMMARY OF THE INVENTION

We have now discovered a new group of compounds (sometimes referred to as secretagogues) that provide desirable in vitro and in vivo growth hormone releasing activity and have at least one other desirable biological activity such as increased retention time. These compounds have the following formulas: A₁-A₂-X  Formula I: wherein A₁ is Aib (aminoisobutyric acid), inip (isonipecotyl) or ABU (aminobutyric acid). The Aib residue can be substituted or unsubstituted. Preferred substituents include C₁-C₆ alkyl and halogens. Aib is preferably unsubstituted. Aib is preferably αAib. ABU is preferably γABU or αγABU, more preferably α,γABU;

-   A₂ is any natural L-amino acid or Pal, or their respective     D-isomers, DαNal (α-naphthyl-D-alanine) or DβNal     (β-naphthyl-D-alanine), preferably A₂ is DTrp, DαNal     (α-naphthyl-D-alanine) or DβNal (βnaphthyl-D-alanine), more     preferably A₂ is DTrp or DαNal; -   X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid,     Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or     any of their respective D-isomers, preferably R₁ is DPro, DTrp,     DβNal or DPhe, more preferably R₁ is DPro or DTrp; and R₂ is     preferably Gly, Phe, Pro, DPro, DPhe, DPal, DLeu, DHis, DVal, DGln,     DArg, DAla, DSer, DThr, DIle, Arg, Orn Lys, Ala, Pal, Thr, Val,     PheCHx, CHxAla or CHx, where x is preferably 1-8, more preferably 1     to 5; and Z is CONH₂ or COOH;     -   (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen, preferably Cl, and R₄         is any natural L-amino acid or Pal, or their respective         D-isomers, preferably R₄ is Phe or Arg, and Z is CONH₂ or COOH;     -   (3) NH(CH₂)_(n)NH, where n is 1 to 8, such as         -2-aminoethylamide, -3-aminopropylamide, -4-aminobutylamide,         -5-aminopentylamide, or -6-aminohexylamide;     -   (4) R₅-R₆, wherein RS is any natural L-amino acid, Pal, αNal,         βNal, DpCl, CHx where x is 1 to 10, or any of their respective         D-isomers, preferably R₅ is DPro or DTrp, and R₆ is         -   (a) diisobutylamide         -   (b) dipropylamide         -   (c) butylamide         -   (d) pentylamide         -   (e) dipentylamide         -   (f) C(═O) (substituted heteroalicyclic or heteroaromatic)             such as -piperidine-3-methyl-benzylether         -   -N-diethylnipectamide         -   -N-piperazine methylsulfonamide         -   -diethylamide         -   -m-methylpiperidine         -   -3,3-diphenylpropylamide         -   -4-piperidino piperidinamide         -   -4-phenyl-piperidinamide         -   -N-methylpiperazine         -   -2-morpholinoethylamine         -   -spiroindole methylsulfonamide         -   -pyrrolidine amide         -   -indoleamide         -   -3-piperidine methanolamide         -   -tropin amide         -   -2-aminoethylamide         -   -3-aminopropylamide         -   -4-aminobutylamide         -   -5-aminopentylamide         -   -6-aminohexylamide;     -   (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to         8, such as -2-aminoethylamide, -3-aminopropylamide,         -4-aminobutylamide, -5-aminopentylamide, or -6-aminohexylamide;         or     -   (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal,         preferably R₈ is DTrp or DPro, R₉ is any natural L-amino acid or         Pal, or their respective D-isomers, preferably R₉ is Phe, DVal,         DPro, DIle, Ile, more preferably R₉ is Phe, DVal or DPro; R₁₀ is         any natural L-amino acid or Pal, or their respective D-isomers,         preferably R₁₀ is Lys or Arg, and Z is CONH₂ or COOH, preferably         Z is CONH₂.         A_(1′)-X′  Formula II:         wherein A_(1′) is Aib, inip, ABU, IMC (imidazole carboxylic         acid), Ava, 4-IMA (Nα-imidazole acetic acid), βAla, Ileu, Trp,         His, DpCl, CHx, or any of their respective D-isomers. The Aib         residue can be substituted or unsubstituted. Preferred         substituents include N- and N-,N-C₁-C₆ alkyl, halogens, N- and         N-,N-2 hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and         3-hydroxyisobutyl. Aib is preferably unsubstituted. Aib is         preferably αAib. ABU is preferably γABU or αγABU, more         preferably α,γABU; and -   X′ is (1) R₁-R₂-Z, wherein R_(1′) is any natural L-amino acid or     Pal, or their respective D-isomers, DαNal or DβNal, preferably     R_(1′) is DTrp, DαNal or DβNal, more preferably R_(1′) is DTrp or     DαNal, and R_(2′) is any natural L-amino acid, Pal, αNal, βNal,     DpCl, Aib, preferably αAib, CHx where x is 1 to 10, or CHxAla, or     any of their respective D-isomers, and Z is CONH₂ or COOH,     preferably Z is CONH₂; or     -   (2) R₃-R_(4′), wherein R_(3′) is any natural L-amino acid or         Pal, or their respective D-isomers, DαNal or DβNal, preferably         R₃ is DPro, DTrp, DαNal or DβNal, more preferably R_(3′) is         DPro, DTrp or DαNal, and R_(4′) is NH(CH₂)_(n)NH, where n is 1         to 8, such as -2-aminoethylamide, -3-aminopropylamide,         -4-aminobutylamide, -5-aminopentylamide, or -6-aminohexylamide.         The organic and inorganic addition salts thereof are also         included.

In an alternative embodiment the compound has the formula A_(1′)-Y,  Formula III: wherein A_(1′) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers. The Aib residue can be substituted or unsubstituted. Preferred substituents include N- and N-,N-C₁-C₆ alkyl, halogens, N- and N-,N-2 hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and 3-hydroxyisobutyl. Aib is preferably unsubstituted. A_(1′) is preferably Aib, inip or ABU. More preferably Aib is αAib. Abu is preferably γAbu or α,γAbu, more preferably α,γAbu.

-   -   Y is A_(2′)-A₃-A₄-A₅-A₆-Z′,     -   A₂′-A₃-A₄-A₅-Z′ or A₂′-A₃-A₄-Z′     -   wherein A_(2′) is A₅-A_(2′) or A₂′,     -   wherein A₅ is a spacer amino acid such as His,     -   A_(2′) is as defined above for A₂. A_(2′) is preferably DTrp,         DαNal or DβNal. A_(2′) is more preferably DTrp.

A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DpCl, D or L (CHX), cyclohexylalanine (CHXAla), or any of their respective D-isomers, preferably A₃ is DPro, DTrp, DβNal or DPhe, more preferably A₃ is DPro or DTrp; and A₄ is preferably Gly, Phe, Pro, Ile, DPro, DPhe, DPal, DLeu, DHis, DVal, DGln, DIle, DNle, DArg, DAla, DSer, DThr, DIle, Arg, Orn Lys, Ala, Pal, Thr, Val, PheCHX, CHXAla or CHX. A₄ is preferably DSer, DAug, DPro, DTrp, DVal, DIle, DThr, DNVal, DNle, Ile, Pro, Phe and still more preferably, A₄ is DPro. A₅ is preferably Ile, Arg, Pal, DArg, DSer, Lys and Arg-DPro. More preferably A₅ is Arg, DArg, and Lys.

Z′ is NH₂, OH or alkylamino or aminoalkylamino, preferably the alkylamino is NH (C₁-C₁₀ alkyl) e.g. NH(CH₂)_(n)CH₃, where n is 1 to 10 such as

N di-(C₁-C₁₀ alkyl) e.g., N di-(CH₂)_(n) CH₃ such as

preferably the aminoalkylamino is a NH(C₁-C₁₀ alkylamino, e.g. NH(CH₂)_(n)NH₂ such as

N(di C₁-C₁₀ alkylamino), e.g., N [di-(CH₂)_(n)NH₂] such as

These compounds can be administered to an animal to promote release of serum growth hormone levels. Thus, these secretagogues can be used in a range of methods for example, to increase milk production, enhance body growth, treat hypothalmic pituitary dwarfism, osteoporosis, burns and renal failure, and to promote wound healing. They can also be used diagnostically. For example, to discover a loss of growth hormone receptor functioning.

DETAILED DESCRIPTION OF THE INVENTION

The compounds described herein are typically easy to synthesize, have efficacy at promoting an increase in serum growth hormone levels, and are desirable for large scale production and utilization. In addition, these compounds may be advantageous in having physiochemical properties which are desirable for the efficient delivery of such polypeptide compounds to a wide variety of animal species because of an improvement in at least one of bioavailability, absorption, metabolism, pharmacokinetics and excretion. The preferred methods of delivery are oral, nasal and continuous delivery utilizing special chemical/mechanical methods of delivery. Pulsed therapy is one preferred method of administration. These compounds have either of the following two formulas: A₁-A₂-X  Formula I: wherein A₁ is Aib (aminoisobutyric acid), inip (isonipecotyl) or ABU (aminobutyric acid). The Aib residue can be substituted or unsubstituted. Preferred substituents include C₁-C₆ alkyl and halogens. Aib is preferably unsubstituted. Aib is preferably αAib. ABU is preferably γABU or αγABU, more preferably α,γABU;

A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal (α-naphthyl-D-alanine) or DβNal (βnaphthyl-D-alanine), preferably A₂ is DTrp, DαNal (α-naphthyl-D-alanine) or DβNal (βnaphthyl-D-alanine), more preferably A₂ is DTrp or DαNal;

-   X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid,     Pal, αNal, βNal, DpCl, CHx, CHxAla, or any of their respective     D-isomers, preferably R₁ is DPro, DTrp, DβNal or DPhe, more     preferably R₁ is DPro or DTrp; and R₂ is preferably Gly, Phe, Pro,     DPro, DPhe, DPal, DLeu, DHis, DVal, DGln, DArg, DAla, DSer, DThr,     DIle, Arg, Orn Lys, Ala, Pal, Thr, Val, PheCHx, CHxAla or CHx, where     x is preferably 1-8, more preferably 1 to 5; and Z is CONH₂ or COOH;     -   (2) DpR₃Phe-R₄-Z, wherein R₃ is a halogen, preferably Cl and R₄         is any natural L-amino acid or Pal, or their respective         D-isomers, preferably R₄ is Phe or Arg, and Z is CONH₂ or COOH;     -   (3) NH(CH₂)_(n)NH, where n is 1 to 8, such as         -2-aminoethylamide, -3-aminopropylamide, -4-aminobutylamide,         -5-aminopentylamide, or -6-aminohexylamide;     -   (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal,         βNal, DpCl, CHx where x is 1 to 10, or any of their respective         D-isomers, preferably R₅ is DPro or DTrp, and R₆ is         -   (a) diisobutylamide         -   (b) dipropylamide         -   (c) butylamide         -   (d) pentylamide         -   (e) dipentylamide         -   (f) C(═O)(substituted heteroalicyclic or heteroaromatic)             such as -piperidine-3-methyl-benzylether         -   -N-diethylnipectamide         -   -N-piperazine methylsulfonamide         -   -diethylamide         -   -m-methylpiperidine         -   -3,3-diphenylpropylamide         -   -4-piperidino piperidinamide         -   -4-phenyl-piperidinamide         -   -N-methylpiperazine         -   -2-morpholinoethylamine         -   -spiroindole methylsulfonamide         -   -pyrrolidine amide         -   -indoleamide         -   -3-piperidine methanolamide         -   -tropin amide         -   -2-aminoethylamide         -   -3-aminopropylamide         -   -4-aminobutylamide         -   -5-aminopentylamide         -   -6-aminohexylamide;     -   (5) DTrp Phe Arg R₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1         to 8, such as -2-aminoethylamide, -3-aminopropylamide,         -4-aminobutylamide, -5-aminopentylamide, or -6-aminohexylamide;         or     -   (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal,         preferably R₈ is DTrp or DPro, R₉ is any natural L-amino acid or         Pal, or their respective D-isomers, preferably R₉ is Phe, DVal,         DPro, DIle, Ile, more preferably R₉ is Phe, DVal or DPro; R₁₀ is         any natural L-amino acid or Pal, or their respective D-isomers,         preferably R₁₀ is Lys or Arg, and Z is CONH₂ or COOH, preferably         Z is CONH₂.         A₁′-X′  Formula II:         wherein A_(1′) is Aib, inip, ABU, IMC (imidazole carboxylic         acid), Ava, 4-IMA (Nα-imidazole acetic acid), βAla, Ileu, Trp,         His, DpCl, CHx, or any of their respective D-isomers. The Aib         residue can be substituted or unsubstituted. Preferred         substituents include N- and N-,N-C₁-C₆ alkyl, halogens, N- and         N-,N-2 hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and         3-hydroxyisobutyl. Aib is preferably unsubstituted. Aib is         preferably αAib. ABU is preferably γABU or αγABU, more         preferably α,γABU; and -   X′ is (1) R₁′-R₂′-Z, wherein R_(1′) is any natural L-amino acid or     Pal, or their respective D-isomers, DαNal or DβNal, preferably     R_(1′) is DTrp, DαNal or DβNal, more preferably R₁ is DTrp or DαNal,     and R_(2′) is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib,     preferably αAib, CHx where x is 1 to 10, or CHxAla, or any of their     respective D-isomers, and Z is CONH₂ or COOH, preferably Z is CONH₂;     or     -   (2) R₃′-R_(4′), wherein R_(3′) is any natural L-amino acid or         Pal, or their respective D-isomers, DαNal or DβNal, preferably         R_(3′) is DPro, DTrp, DαNal or DβNal, more preferably R_(3′) is         DPro, DTrp or DαNal, and R_(4′) is NH(CH₂)_(n)NH, where n is 1         to 8, such as -2-aminoethylamide, -3-aminopropylamide,         -4-aminobutylamide, -5-aminopentylamide, or -6-aminohexylamide.         The organic and inorganic addition salts thereof are also         included.

The abbreviations for the residues of amino acids used herein are in agreement with the standard nomenclature, and are set forth below:

Gly Glycine Tyr L-Tyrosine Ile L-Isoleucine Glu L-Glutamic Acid Thr L-Threonine Phe L-Phenylalanine Ala L-Alanine Lys L-Lysine Asp L-Aspartic Acid Cys L-Cysteine Arg L-Arginine Gln L-Glutamine Pro L-Proline Leu L-Leucine Met L-Methionine Ser L-Serine Asn L-Asparagine His L-Histidine Trp L-Tryptophan Val L-Valine Orn L-Ornithine

Moreover, all of the three letter-abbreviations of the amino acids preceded by a “D” indicate the dextro-isomer of the aminoacidic residue, and glycine is considered to be included in the term naturally occurring L-amino acids. Other abbreviations used herein include the following:

Aib aminoisobutyric acid inip isonipecotyl ABU aminobutyric acid αNal α-naphthyl alanine βNal β-naphthyl alanine DαNal α-naphthyl-D-alanine DβNal β-naphthyl-D-alanine Pal 3-pyridyl alanine CHx cyclohexyl CHxAla L-cyclohexylalanine Ava Aminovaleric acid IMA Nα-imidazole acetic acid IMC imidazole carboxylic acid βAla β-Alanine

In one embodiment of the present invention, a group of preferred compounds includes:

-   γABUDTrpDTrpArgCOOH -   α,γABUDTrpDTrpArgNH₂ -   α,γABUDTrpDTrpOrnNH₂ -   α,γABUDαNalDTrpLysNH₂ -   α,γABUDαNalDTrpArgNH₂ -   α,γABUDαNalDTrpArgNH₂ -   αAibDTrpDTrpArgNH₂ -   αAibDαNalDTrpArgNH₂ -   αAibDTrpDTrpArgCOOH -   αAibDαNalDTrpArgCOOH -   αAibDaTrpDTrpArgNH₂ -   αAibDTrpDPheArgNH₂ -   inipDαNalDTrpPheNH₂ -   inipDαNalDTrpCHxAlaNH₂ -   inipDαNalDTrpPheCOOH -   inipDαNalDTrpPalNH₂ -   inipDαNalDTrpThrNH₂ -   inipDαNalDTrpValNH₂ -   inipDαNalDNalPheNH₂ -   inipDαNalDTrpPheCOOH -   inipDβNalDTrpPheNH₂ -   αAibDTrpDProGlyNH₂ -   αAibDTrpDProPheNH₂ -   αAibDTrpDProProNH₂ -   αAibDTrpDProDProNH₂ -   αAibDTrpDProDPheNH₂ -   αAibDTrpDProDPalNH₂ -   αAibDTrpDProDTrpNH₂ -   αAibDTrpDProDLeuNH₂ -   αAibDTrpDProDHisNH₂ -   αAibDTrpDProDValNH₂ -   αAibDTrpDProGlnNH₂ -   αAibDTrpDProArgNH₂ -   αAibDTrpDProLysNH₂ -   αAibDTrpDProDAlaNH₂ -   inipDαNalDpClPhePheNH₂ -   inipDαNalDpClPheArgNH₂ -   inipDαNalDTrpDProNH₂ -   αAibDTrpDProDSerNH₂ -   αAibDTrpDProDThrNH₂ and -   αAibDTrpDProDIleNH₂.

In another embodiment of the present invention, a group of preferred compounds includes:

-   inipDTrpDTrpPheLysNH₂ -   inipDβNalDTrpPheLysNH₂ -   γABUDβNalDTrpPheLysNH₂ -   α,γABUDTrpDTrpPheLysNH₂ -   βAlaDTrpDTrpPheLysNH₂ -   α,γABUDPNalDTrpPheLysNH₂ -   α,γABUDTrpDTrpPheArgNH₂ -   α,γABUDαNalDTrpPheArgNH₂ -   inipDβBNalDTrpPheLysNH₂ -   inipDTrpDTrpPheArgNH₂ -   βAlaDαNalDTrpPheArgNH₂ -   αAibDTrpDTrpPheArgNH₂ -   αAibDTrpDTrpPheArgCOOH -   inipDTrpDTrpPheArgCOOH -   inipDαNalDTrpPheArgNH₂ -   inipDαNalDTrpPheArgCOOH -   inipDαNalDβNalPheArgNH₂ -   inipDαNalDTrpPheDSerNH₂ -   inipDαNalDTrpPheDThrNH₂ -   inipDαNalDTrpPheGlyNH₂ -   inipDαNalDTrpPheGlnNH₂ -   inipDαNalDTrpPheDGlnNH₂ -   αAibDαNalDTrpPheGlnNH₂ -   inipDαNalDTrpPheDHisNH₂ -   αAibDTrpDProPheArgNH₂ -   αAibDTrpDProPheDArgNH₂ -   αAibDTrpDProDValArgNH₂ -   αAibDTrpDProDValDLysNH₂ -   αAibDTrpDProDValDArgNH₂ -   αAibDTrpDProDProArgNH₂ -   αAibDTrpDProDProDPalNH₂ -   αAibDTrpDProDProDArgNH₂ -   αAibDTrpDProDIleDArgNH₂ -   αAibDTrpDProDIleArgNH₂ -   αAibDTrpDProDProDLysNH₂ and -   αAibDTrpDProIleArgNH₂.

In the above Formula I, where X is R₅-R₆ and R₆ is a C(═O) (substituted heteroalicyclic or heteroaromatic), the heteroatom is selected from the group consisting of O, N, S and P.

The heteroalicyclic moiety preferably contains 2 to 12 carbon atoms, more preferably 3 to 8 carbon atoms. The heteroaromatic moiety preferably contains 5 to 12 carbon atoms, more preferably 5 to 11 carbon atoms. Substituents include NH₂, C₁-C₁₂ lower alkyl, and as listed below.

Examples include piperidine-3-methyl-benzylether, N-diethylnipectamide, N-piperazine methylsulfonamide, diethylamide, m-methylpiperidine, 3,3-diphenylpropylamide, 4-piperidino piperidinamide, 4-phenyl-piperidinamide, N-methyl 1-piperiazine, 2-morpholinoethylamine, spiroindole methylsulfonamide, pyrrolidine amide, indoleamide, 3-piperidine methanol amide, tropin amide, 2-aminoethylamide, 3-aminopropylamide, 4-aminobutylamide, 5-aminopentylamide, 6-aminohexylamide. Preferred substituted heteralicyclic or heteroaromatic include N-diethylnipectamide, piperidine-3-methyl-benzylether, N-piperazine methyl sulfonamide, diethylamide and m-methylpiperidine. Even more preferred are N-diethylnipectamide and piperidine-3-methyl-benzylether.

Preferably, the compound has the structure AibDTrpX, where X is DProNH₂, DPro-diisobutylamide, DProbutylamide, DPro-C(═O)(substituted heteroalicyclic or heteroaromatic), and DTrp-Phe-Arg-5-aminopentamide and organic and inorganic addition salts thereof. More preferably, X is DPro-diisobutylamide, DPro-C(═O)(substituted heteroalicyclic or heteroaromatic) and DTrp PheArg-5-aminopentamide, and organic and inorganic addition salts thereof. Still more preferably, X is DPro-diisobutylamide or DTrp-Phe-Arg-5-aninopentamide, and organic and inorganic addition salts thereof. Even more preferably, X is DPro-diisobutylamide and organic and inorganic addition salts thereof.

In an alternative embodiment the compound has the formula A_(1′)-Y, wherein A_(1′) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers. The Aib residue can be substituted or unsubstituted. Preferred substituents include N- and N-,N-C₁-C₆ alkyl, halogens, N- and N-,N-2 hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and 3-hydroxyisobutyl. Aib is preferably unsubstituted. A_(1′) is preferably Aib, inip or ABU. More preferably Aib is αAib. Abu is preferably γAbu or α,γAbu, more preferably α,γAbu.

-   -   Y is A_(2′)-A₃-A₄-A₅-A₆-Z′,     -   A_(2′)-A₃-A₄-A₅-Z′ or A₂.-A₃-A₄-Z′     -   wherein A_(2′) is A₅-A_(2′) or A_(2′),     -   wherein A₅ is a spacer amino acid such as His,     -   A_(2′) is as defined above for A₂. A_(2′) is preferably DTrp,         DαNal or DβNal. A₂′ is more preferably DTrp.

A3, A4 and A5 are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DpCl, D or L (CHX), cyclohexylalanine (CHXAla), or any of their respective D-isomers, preferably A₃ is DPro, DTrp, DβNal or DPhe, more preferably A₃ is DPro or DTrp; and A₄ is preferably Gly, Phe, Pro, Ile, DPro, DPhe, DPal, DLeu, DHis, DVal, DGln, DIle, DNle, DArg, DAla, DSer, DThr, DIle, Arg, Orn Lys, Ala, Pal, Thr, Val, PheCHX, CHXAla or CHX. A₄ is preferably DSer, DAug, DPro, DTrp, DVal, DIle, DThr, DNVal, DNle, Ile, Pro, Phe and still more preferably, A₄ is DPro. A₅ is preferably Ile, Arg, Pal, DArg, DSer, Lys and Arg-DPro. More preferably A₅ is Arg, DArg, and Lys.

Z′ is NH₂, OH or (aminoalkyl) or (aminoalkylamino), preferably the aminoalkyl is NH(C₁-C₁₀ alkyl) e.g. NH(CH₂)_(n)CH₃, where n is 1 to 10 such as

N di-(C₁-C₁₀ alkyl) e.g., N di-(CH₂)_(n)CH₃ such as

preferably the alkylamino is a NH(C₁-C₁₀ alkylamino, e.g. NH(CH₂)_(n)NH₂ such as

N (di C₁-C₁₀ alkylamino), e.g., N[di-(CH₂)_(n)NH₂] such as

Preferred examples include moieties such as -2-aminoethylamide, -3-aminopropylamide, -4-aminobutylamide, -5-aminopentylamide, or

-   -   -6-aminohexylamide; N-dimethylamide; N-diethylamide;         N-dipropylamide; N-dibutylamide; N-diisobutylamide;         N-dipentylamide; N-dihexylamide;

A particularly preferred embodiment is Aib-Y, more preferably αAib-Y.

Y is preferably A_(2′)-DPro-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-Z′; or A_(2′)-A₃-A₄-A₅-Z′. Y is more preferably A₂′-DPro-A₄-Z′ or A₂′, -DPro-A₄-Z′ or A_(2′)-DPro-A₄-A₅-Z′. Still more preferably Y is A_(2′)-DPro-A₄-A₅-Z′. Z′ is preferably —NH₂.

Preferred embodiments include

-   αAib-DTrp-DPro-A₄-A₅-A₆-Z′; -   αAib-DTrp-DPro-A₄-A₅-Z′; -   αAib-DTrp-DPro-A₄-Z′; -   αAib-DTrp-DPro-A₄-Arg-NH₂; -   αAib-DTrp-DPro-A₄-Arg-A₆-NH₂; -   αAib-DTrp-DPro-A₄-Arg-Gly-NH₂; -   αAib-DαNal-DPro-A₄-A₅-A₆-Z′; -   αAib-DαNal-DPro-A₄-A₅-Z′; -   αAib-DαNal-DPro-A₄-Z′; -   αAib-DαNal-DPro-A₄-NH₂; -   αAib-DαNal-DPro-A₄-Arg-NH₂; -   and αAib-DαNal-DPro-A₄-Arg-Gly-NH₂.

A₄ is preferably DIle, DThr, DNle, DVal, DGln, DAla, DPhe, DTrp, DNVal and Arg.

Exemplery representatives of αAib-A_(2′)-DPro-A₄-Arg-Z′ include

-   αAibDTrpDProDIleArgNH₂; -   αAibDTrpDProDThrArgNH₂; -   αAibDTrpDProDValArgNH₂; -   αAibDTrpDProDNleArgNH₂; and -   αAibDαNalDProDIleDArgNH₂.

Exemplary representatives of:

-   αAib-A₂′-DPro-A₄-Z include -   αAib-DTrp-DPro-DThr-NH₂; -   αAib-DTrp-DPro-DGln-NH₂; -   αAib-DTrp-DPro-Arg-NH₂; -   αAib-DTrp-DPro-DAla-NH₂; -   αAib-DTrp-DPro-DPhe-NH₂; -   αAib-DTrp-DPro-DTrp-NH₂; -   αAib-DTrp-DPro-DVal-NH₂; -   αAib-DTrp-DPro-DNVal-NH₂; and -   αAib-DTrp-DPro-DIle-NH₂;

Exemplary representatives of αAib-A_(2′)-DPro-A₄-Arg-A₆-Z include compounds of the formula αAib-A_(2′)-DPro-A₄-Arg-Gly-NH₂ such as

-   αAib-DTrp-DPro-DIle-Arg-Gly-NH₂; -   αAib-DTrp-DPro-DThr-Arg-Gly-NH₂; and -   αAib-DTrp-DPro-DNle-Arg-Gly-NH₂.

Representative compounds are set forth below:

-   inipDαNalDTrpNH₂; -   inipDαNalDValNH₂; -   αAibDTrpDValNH₂; -   αAibDTrpDProDSerNH₂; -   αAibDTrpDProDArgNH₂; -   αAibDTrpDProDPheNH₂; -   αAibDTrpDProDTrpNH₂; -   αAibDTrpDValDValNH₂; -   αAibDValDProDValNH₂; -   αAibDValDValDValNH₂; -   αAibDTrpDProDLysNH₂; -   αAibDProDProDValNH₂; -   inipDαNalDTrpDValNH₂; -   αAibDTrpDProIleNH₂; -   αγAbuDαNalDTrpDIleNH₂; -   inipDaNalDTrpDProIleNH₂; -   ipDaNalDTrpPheIleNH₂; -   inipDαNalDTrpDValArgNH₂; -   αAibDTrpDProDValDValNH₂; -   αAibDTrpDProDProDPalNH₂; -   αAibDTrpDProDValArgDProNH₂; -   αAibDTrpDProDIleDArgNH₂; -   αAbuDTrpDTrpDIleNH₂; -   inipDαNalDTrpPheDValNH₂; -   αAibDTrpDProValNH₂; -   αAibDTrpDIleDIleNH₂; -   αAibDTrpDProLeuNH₂; -   αAibDTrpDProThrNH₂; -   DHisDTrpDProDValArgNH₂; -   DHisDTrpDProDThrNH₂; -   αAibDTrpDProDIleNH₂; -   αAibDTrpDPheDValNH₂; -   αLibDTrpDProDValDArgNH₂; -   αAibDTrpDProDAlaNH₂; -   αAibDTrpDProDProNH₂; -   αAibDTrpDProArgNH₂; -   αAibDTrpDProDValNH₂ -   inipDαNalDTrpDProNH₂; -   αAibDαNalDProDValDArgNH₂; -   αAibDαNalDProDIleDArgNH₂; -   αAibDTrpDProDProDLysNH₂; -   αAibHisDαNalDPheLysNH₂; -   αAibHisDTrpDProDValNH₂; -   αAibHisDTrpDProDIleNH₂; -   αAibHisDTrpDProValArgNH₂; -   αAibHisDTrpDProDValArgNH₂; -   αAibDαNalDProDValNH₂; -   αAibDTrpDProDThrArgNH₂; -   αAibDTrpDProDNleArgNH₂; -   αAibDTrpDProDNValArgNH₂; -   αAibDTrpDProIleArgNH₂; -   αAibDTrpDProDProArgNH₂; -   αAibDTrpDProProArgNH₂; -   αAibDTrpDProDProDArgNH₂; -   αAibDTrpDProDIleArgNH₂; -   αAibDTrpDProPheDSerNH₂; -   αAibDTrpDProPheArgNH₂; -   αAibDTrpDProDValArgNH₂; -   SarDTrpDTrpPheArgNH₂; -   αAibDαNalDProDProArgNH₂; -   αAibDαNalDProDNValArgNH₂; -   αAibDαNalDProDIleArgNH₂; -   αAibDαNalDProDValLysNH₂; -   αAibDαNalDProDThrArgNH₂; -   αAibDαNalDProDThrArgNH₂; -   αAibDαNalDProDValArgNH₂; -   αAibDαNalDProDValArgNH₂; -   αAibDTrpDProDNleNH₂; -   αAibDTrpDProDNValNH₂. -   αAibDTrpDProDIle-X_(a), where X_(a) is -   2-aminoethylamide, -   5-aminopentylamide, or -   3-aminopropylamide. -   αAibDTrpDProDVal-X_(b), where X_(b) is -   2-aminoethylamide, -   dimethylamide, or -   diethylamide. -   αAibDTrpDProDPro-X_(c), where X_(c) is -   2-aminoethylamide.

The following compounds are preferred

-   αAibDTrpDProDIleXd, where X_(d) is -   5-aminopentylamide, -   3-aminopropylamide, -   2-aminoethylamide, or -   4-aminobutylamide -   αAibDTrpDProDValX_(e), where X_(e) is -   N-dimethylamide, -   N-diethylamide, or -   2-aminoethylamide; -   αAibDTrpDProDValX_(f), where X_(f) is -   5-aminopentylamide; -   αAibDTrpDProDNleX_(g), where X_(g) is -   5-aminopentylamide; -   αAibDTrpDProDProArgNH₂; -   αAibDTrpDProDValDArgNH₂; -   αAibDTrpDProDValArgNH₂; -   αAibDTrpDProDIleArgNH₂; -   αAibDαNalDProDValArgNH₂; -   αAibDαNalDProDValArgNH₂; -   αAibDαNalDProDIleArgNH₂; -   αAibDαNalDProDValLysNH₂; -   inipDαNalDαNalPheArgNH₂; -   αAibDTrpDProDThrArgNH₂; -   αAibDTrDProDNleArgNH₂; -   αAibDTrpDProDNValArgNH₂; -   αAibDTrpDProDIleArgGlyNH₂; -   αAibDTrpDProDProDIleArgGlyNH₂; -   αAibDTprDProDNleArgGlyNH₂; and -   αAibDTrpDProDThrArgGlyNH₂;

In one embodiment one uses compound from compounds having the formula

-   αAibDTrpDProDProA₄ArgNH₂ or -   αAibDTrpDProDProA₄ArgGlyNH₂.

Preferred examples are selected from the group consisting of

-   αAibDTrpDProDIleArgNH₂ -   αAibDTrpDProDIleArgGlyNH₂ -   αAibDTrpDProDProDIleArgNH₂, and -   αAibDTrpDProDProDIleArgGlyNH₂.

In an alternate embodiment, the following peptides are of interest:

-   DβNaldaTrpDPheLysGlnGlyNH₂ -   DAlaDTrpAlaTrpDPheLysValGlyNH₂ -   DAlaDβNaLAlaTrpDPheLysGlnGlyGlyGlyNH₂ -   DAlaDTrpAlaTrpDPheLysHisGlyNH₂

These secretagogues can be used therapeutically for any use for which growth hormone can be used, such as treating hypothalamic pituitary dwarfism, osteoporosis, burns, and renal failure for acute use, for non-union bone fracture, and to promote wound healing. Additionally, it can be used to promote recovery from surgery, and acute/chronic debilitating medical illnesses. Beneficial anabolic effects result on skin, muscle and bone in relation to the aging process with a concomitant decrease in body fat. Treatment of cancer patients by these peptides is also included, for example, prevention and/or reduction of cachexia in cancer patients. These therapeutic uses are accomplished by using a therapeutically effective amount of the compound. Such an amount is that needed to promote the release of serum growth hormone levels as discussed, infra.

The compounds of this invention may also be used to enhance blood GH levels in animals; enhance milk production in cows; enhance body growth in animals such as, e.g., humans, sheep, bovines, and swine, as well as fish, fowl, other vertebrates and crustaceans; and increase wool and/or fur production in mammals. The amount of body growth is dependent upon the sex and age of the animal species, quantity and identity of the growth hormone releasing compound being administered, route of administration, and the like.

Also, the compounds of this invention increase serum GH in humans; enhance body growth in short stature children; decrease body fat and improve protein metabolism in select children; improve protein metabolism of the skin, muscle, bone while decreasing body fat of the elderly, particularly when GH deficiency is present.

These compounds are also useful for improving serum lipid pattern in humans by decreasing in the serum the amount of serum cholesterol and low density lipoprotein, and increasing in the serum the amount of the high density lipoprotein.

The novel secretagogues of this invention can be synthesized according to the usual methods of solution and solid phase peptide chemistry, or by classical methods known in the art.

In accordance with another embodiment of the present invention, a method is provided for promoting release and/or elevation of growth hormone levels in the blood of an animal. This method of promoting the release and/or elevation of growth hormone levels can also be used to therapeutically treat the aforesaid diseases. Said methods comprise administering to an animal an effective dose of at least one of the above-described compounds. In one embodiment, this method is used in animals other than humans.

The compounds of this invention can be administered by oral, parenteral (intramuscular (i.m.), intraperitoneal (i.p.), intravenous (i.v.) or subcutaneous (s.c.) injection), nasal, vaginal, rectal or sublingual routes of administration as well as intrapulmonary inhalation can be formulated in dose forms appropriate for each route of administration. Parenteral administration is preferred.

Solid dose forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dose forms, the active compound is mixed with at least one inert carrier such as sucrose, lactose, or starch. Such dose forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dose forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dose forms for oral administration include emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides, such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.

Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dose forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in a medicum of sterile water, or some other sterile injectable medium immediately before use.

The amount of secretagogues or combination of compounds of the present invention administered will vary depending on numerous factors, e.g., the particular animal treated, its age and sex, the desired therapeutic affect, the route of administration and which polypeptide or combination of polypeptides are employed. In all instances, however, a dose effective (therapeutically effective amount) to promote release and elevation of growth hormone level in the blood of the recipient animal is used. Ordinarily, this dose level falls in the range of between about 0.1 μg to 10 μg of total compound per kg of body weight. The preferred amount can readily be determined empirically by the skilled artisan based upon the present disclosure.

For example, in humans when the mode of administration is i.v. the preferred dose level falls in the range of about 0.1 μg to 10 μg of total secretagogue per kg of body weight, more preferably, about 0.5 μg to 5 μg of total secretagogue per kg of body weight, still more preferably about 0.7 μg about 3.0 μg per kg of body weight. When combinations of growth hormone releasing compounds are used, lower amounts of the presently described peptide can be used. For example, combining the presently described secretagogues with, for example, a synergistic compound in Group I of U.S. Pat. No. 4,880,778 such as GHRH, or U.S. Pat. No. 5,663,146 or U.S. Pat. No. 5,486,505, a preferred range is about 0.1 μg to about 5 μg of the presently described compound per kg of body weight and about 0.5 μg to about 15.0 μg of synergistic compound (e.g. GHRH) and more preferably about 0.1 μg to about 3 μg of the present compound with about 1.0 μg to about 3.0 μg of the synergistic compound per kg of body weight.

When the mode of administration is oral, greater amounts are typically needed. For example, in humans for oral administration, the dose level is typically about 30 μg to about 1200 μg of compound per kg of body weight, more preferably about 70 μg to about 600 μg of compound per kg of body weight, still more preferably, about 200 μg to about 600 μg of total compound per kg of body weight. Cows and pigs require about the same dose level as humans, while rats typically require higher dose levels. The exact level can readily be determined empirically based upon the present disclosure.

In general, as aforesaid, the administration of combinations of growth hormone releasing peptides will allow for lower doses of the individual growth hormone releasing compounds to be employed relative to the dose levels required for individual growth hormone releasing compounds in order to obtain a similar response, due to the synergistic effect of the combination.

Also included within the scope of the present invention are compositions that comprise, as an active ingredient, the organic and inorganic addition salts of the above-described polypeptides and combinations thereof; optionally, in association with a carrier, diluent, slow release matrix, or coating.

The organic or inorganic addition salts of the growth hormone releasing compounds and combinations thereof contemplated to be within the scope of the present invention include salts of such organic moieties as acetate, trifluoroacetate, oxalate, valerate, oleate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, and the like; and such inorganic moieties as Group I (i.e., alkali metal salts), Group II (i.e. alkaline earth metal salts) ammonium and protamine salts, zinc, iron, and the like with counterions such as chloride, bromide, sulfate, phosphate and the like, as well as the organic moieties referred to above.

Pharmaceutically acceptable salts are preferred when administration to human subjects is contemplated. Such salts include the non-toxic alkali metal, alkaline earth metal and ammonium salts commonly used in the pharmaceutical industry including sodium, potassium, lithium, calcium, magnesium, barium, ammonium and protamine salts which are prepared by methods well known in the art. The term also includes non-toxic acid addition salts which are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate and the like.

The invention will be further illustrated by the following non-limiting examples.

EXAMPLES OF THE INVENTION

The following examples are designed to illustrate certain aspects of the present invention. The examples are not intended to be comprehensive of all features and all embodiments of the present invention, and should not be construed as limiting the claims presented herein.

General Methods for Synthesis

1H NMR spectra were measured (SiMe₄ internal standard) on a GE-500 (500 MHz) Spectrometer. Mass spectra data were obtained by using a “Lasermat” Laser Desorption Mass Spectrometry. Reagents were obtained from commercial sources and used without further purification. Solvents were dried according to standard procedures. Scheme 1 can be utilized for additions with any amine group recorded in Table 1.

Example 1

Synthesis of the Growth Hormone Releasing Peptides

Paramethyl benzhydrylamine hydrochloride (pMe-BHA HCl) resin is placed in a reaction vessel on a commercially available automated peptide synthesizer. The resin is substituted with free amine up to a loading of about 5 mmoles per gram. The compounds are prepared by coupling individual amino acids starting at the carboxy terminus of the peptide sequence using an appropriate activating agent, such as N,N′ dicyclohexylcarbodiimide (DCC). The alpha amine of individual amino acids are protected, for example, as the t-butyloxycarbonyl derivative (t-Boc) and the reactive side chain functionalities are protected as outlined in Table 1.

TABLE 1 Side Chain Protecting Groups Suitable for Solid Phase Peptide Synthesis Arginine N_(g) -Tosyl Aspartic Acid O-Benzyl Cysteine S-para-Methylbenzyl Glutamic Acid O-Benzyl Histidine N^(im)-Tosyl Lysine N^(ε)-2,4-Dichlorobenzyloxycarbonyl Methionine S-Sulfoxide Serine O-Benzyl Threonine O-Benzyl Tryptophan N^(in)-Formyl Tyrosine O-2,6-Dichlorobenzyl

Prior to incorporation of the initial amino acid, the resin is agitated three times (about one minute each) with dichloromethane (CH₂C₁₂: about 10 ml/gm of resin), neutralized with three agitations (about two minutes each) of N,N-diisopropylethylamine (DIEA) in dichloromethane (10:90; about 10 ml/gm of resin) and agitated three times (about one minute each) with dichloromethane (about 10 mL/gm of resin). The initial and each of the subsequent amino acids are coupled to the resin using a preformed symmetrical anhydride using about 6.0 times the total amount of the reaction capacity of the resin of a suitably protected amino acid and about 2.0 times the total amount of the binding capacity of the resin of DIC in an appropriate amount of dichloromethane. For amino acids with a low dichloromethane solubility, N,N-dimethylformamide (DMF) is added to achieve a homogenous solution. Generally, the symmetrical anhydride is prepared up to 30 minutes prior to introduction into the reaction vessel at room temperature or below. The dicyclohexylurea that forms upon preparation of the symmetrical anhydride is removed via gravity filtration of the solution into the reaction vessel. Progress of the coupling of the amino acid to the resin is commonly monitored via a color test using a reagent such as ninhydrin (which reacts with primary and secondary amines). Upon complete coupling of the protected amino acid to the resin (>99%), the alpha amine protecting group is removed by treatment with acidic reagent(s). A commonly used reagent consists of a solution of trifluororacetic acid (TFA) in dichloromethane (33:66).

After the desired amino acid sequence has been completed, the desired peptide can be cleaved from the resin support by treatment with a reagent such as hydrogen fluoride (HF) which not only cleaves the peptide from the resin, but also cleaves most commonly used side-chain protecting groups. When the BHA or p-Me-BHA resin is used, HF treatment results directly in free peptide amides. When an amino acid-Merrifield resin is used, free peptide alkylamides are cleaved by treatment with an appropriate amine (in this case, use of Boc-N^(ε). FMOC-Lys would allow simultaneous removal of the FMOC group).

The complete procedure for incorporation of each individual amino acid residue onto the resin is outlined in Table 2.

TABLE 2 Procedure for Incorporation of Individual Amino Acids onto a Resin Reagent Agitations Time/Agitation 1. Dichloromethane 3 1 min. 2. TFA-Dichloromethane 1 2 min. (33:66) 3. TFA-Dichloromethane 1 20 min. (33:66) 4. Dichloromethane 3 1 min. 5. DIEA, DMF 2 2 min. (10:90) 6. Dichloromethane 3 1 min. 7. Boc amino acid/DIC 1 15–120 min* 8. Dichloromethane 3 1 min. 10. Monitor progress of the coupling reaction** 11. Repeat steps 1–12 for each individual amino acid *Coupling time depends upon the individual amino acid. **The extent of coupling can be generally monitored by a color test. If the coupling is incomplete, the same amino acid can be recoupled by a different protocol, e.g. HOBt active ester. If the coupling is complete the next amino acid can then be coupled.

Using this procedure the compounds described in Tables 3, 4 and 5 were made.

Example 2 In Vivo GH Release in Rats

Immature female Sprague-Dawley rats were obtained from the Charles River Laboratories (Wilmington, Mass.). After arrival they were housed at 25° C. with a 14:10 hour light:dark cycle. Water and Purina rat chow were available ad libitum. Pups were kept with their mothers until 21 days of age.

Twenty-six day old rats, six rats per treatment group, were anesthetized interperitoneally with 50 mg/kg of pentobarbital 20 minutes prior to i.v. treatment with peptide. Normal saline with 0.1% gelatin was the vehicle for intravenous (i.v.) injections of the peptides. The anesthetized rats, weighing 55-65 grams, were injected i.v. with the quantity of grown hormone releasing compounds indicated in Table 3. Injection was made as a 0.1 mL solution into the jugular vein.

All animals were sacrificed by guillotine 10 minutes after final test injection (see Table 3). Trunk blood for the determination of blood GH levels was collected following decapitation. After allowing the blood to clot, it was centrifuged and the serum was separated from the clot. Serum was kept frozen until the day of sampling for radioimmunoassay (RIA) determination of growth hormone levels according to the following procedure, as developed by the National Institute of Arthritis, Diabetes and Digestive and Kidney Diseases (NIADDK).

Reagents are generally added to the RIA analysis tubes at a single sitting, at refrigerator temperature (about 4° C.) in the following sequence:

-   -   (a) buffer,     -   (b) “cold” (i.e., non-radioactive) standard or unknown serum         sample to be analyzed,     -   (c) radio-iodinated growth hormone antigen, and     -   (d) growth hormone antiserum.

Reagent addition is generally carried out so that there is achieved a final RIA tube dilution of about 1:30,000 (antiserum to total liquid volume; vol:vol).

The mixed reagents are then typically incubated at room temperature (about 25° C.) for about 24 hours prior to addition of a second antibody (e.g., goat or rabbit anti-monkey gamma globulin serum) which binds to and causes precipitation of the complexed growth hormone antiserum. Precipitated contents of the RIA tubes are then analyzed for the number of counts in a specified period of time in a gamma scintillation counter. A standard curve is prepared by plotting number of radioactive counts versus growth hormone (GH) level. GH levels of unknown are then determined by reference to the standard curve.

Serum GH was measured by RIA with reagents provided by the National Hormone and Pituitary Program.

Serum levels in Tables 3 and 4 are recorded in ng/mL in terms of the rat GH standard of 0.61 International Units/mg (IU/mg). Data is recorded as the mean ±standard error of the mean (SEM). Statistical analysis was performed with Student's t-test. In Table 3, the results shown are the average of studies with six rats.

Example 3 Synthesis of Aib-DTrp-DPro-diisobutylamide (YL-156)

(1) Synthesis of DPro-Diisobutylamide (1):

1 mmol of Boc-DPro (Boc=tert-Butoxycarbonyl group) was dissolved in 30 ml dry CH₂Cl₂ in a 100 ml round bottom flask, with 1 mmol of 1-hydroxybenzotriazole added while stirring under N₂ atmosphere in an ice-bath, then 1.05 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCl was added in 10 ml dry CH₂Cl₂ at a fast drop rate and the reaction mixture was stirred for 1 hour at 0° C. 1.1 mmol of diisobutylamine in 10 ml of CH₂Cl₂ was added dropwise and stirring was continued for a further 18 h at ambient temperature. The reaction mixture was washed with 20 ml of 20% aqueous citric acid, 20 ml of saturated aqueous NaHCO₃, and 20 ml of saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Further purification was done by flash column chromatography (SiO₂, CHCl₃/MeOH, 95:5) to afford white solid of Boc-DPro-diisobutylamide.

Under N₂ atmosphere, the Boc-DPro-diisobutylamide was dissolved in 25 ml of CH₂Cl₂ and 1-ml of trifluoracetic acid was added while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH₂Cl₂ and washed with 10 ml saturated NaHCO₃ aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH₂Cl₂ (3×10 ml). The organic layer was dried over anhydrous sodium sulfate and filtered and the solvent was removed in vacuum. The residue was further purified by column chromatography (SiO₂, CHCl₃/MeOH, 85:15) to afford 0.73 mmol (73%) of compound (1) which was characterized by TLC on mass spectra, M⁺=225.1.

(2) Synthesis of DTrp-DPro-diisobutylamide (2):

In a 100 ml round bottom flask, 0.70 mmol of Boc-DTrp was dissolved in ml dry CH₂Cl₂ and 0.70 mmol of 1-hydroxybenzotriazole was added while stirring under N₂ atmosphere in an ice-bath then 0.75 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCl was added in 15 ml dry CH₂Cl₂ at a fast drop rate and the reaction mixture stirred for 1 hour at 0° C. 0.71 mmol of (1) in 20 ml of CH₂Cl₂ was added dropwise and stirring was continued for a further 18 h at ambient temperature. The reaction mixture was washed with 20 ml of 20% citric acid aqueous solution, 20 ml of saturated NaHCO₃ aqueous solution, and 20 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filters and concentrated by vacuum. Further purification was done by flash column chromatography (CHCl₃/MeOH, 95:5) to afford white solid of Boc-DTrp-D-diisobutylamide.

Under N₂ atmosphere, the Boc-DTrp-DPro-diisobutylamide was dissolved in 25 ml of CH₂Cl₂, 1 ml of methylsulfide and 0.5 ml of 1,2-ethanedithiol was added as scavenger in suppressing the indole alkylation of tryptophane. 10 ml of trifluoracetic acid was added dropwise while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH₂Cl₂ and washed with 10 ml saturated NaHCO₃ aqueous solution. The organic layer was dried over anhydrous sodium sulfate and filtered and the solvents were removed in vacuum. The residue was further purified by column chromatography (SiO₂, CHCl₂/MeOH, 85:15) to afford 0.55 mmol (78.5%) of compound (2) which was characterized by TLC and mass spectra, M⁺=411.5.

(3) Synthesis of Aib-DTrp-DPro-diisobutylamide (YL-156):

In a 100 ml round bottom flask, 0.50 mmol of Boc-Aib (Aib=α-aminoisobutyric acid) was dissolved in 30 ml dry CH₂Cl₂ and then 0.51 mmol of 1-hydroxybenzotrizole was added while stirring under N₂ atmosphere in an ice-bath, 0.55 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCl was added in 20 ml dry CH₂Cl₂ at a fast drop rate and the reaction was stirred for 1 hour at 0° C. 0.51 mmol of (2) in 15 ml of CH₂Cl₂ was added dropwise and stirring was continued for a further 18 h at ambient temperature. The reaction mixture was washed with 20 ml of 20% citric acid aqueous solution, 20 ml of saturated NaCHO₃ aqueous solution, and 20 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Further purification was done by flash column chromatography (CHCl₃/MeOH, 95:5) to afford white solid of Boc-Aib-DTrp-DPro-diisobutylamide.

Under N₂ atmosphere, the Boc-Aib-DTrp-DPro-diisobutylamide was dissolved in 30 ml of CH₂Cl₂, 1 ml of methylsulfide and 0.5 ml of 1,2-ethanedithiol were added as scavengers to suppress the indole alkylation of tryptophan. 10 ml of trifluoracetic acid was added dropwise while being stirred. The reaction mixture was stirred for 30 min. Volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH₂Cl₂ and washed with 10 ml saturated NaHCO₃ aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH₂Cl₂ (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered and the solvents were removed in vacuum. The residue was further purified by column chromatography (SiO₂, CHCl/MeOH, 85:15) to afford 0.43 mmol (86.2%) of compound (YL-156) which was characterized by TLC and mass spectra M⁺=497.6.

Example 4 Synthesis of inip-DαNal-DTrp-Phe-2-aminoethylamide YL-105)

3.5 g of Wang resin with the peptide attached was supplied by Research Genetics Laboratory. It was added to a 100 ml round-bottom flask and then sequentially 40 ml of dry CH₂Cl₂, 4 ml of methanol and 2 ml of 1,2-diaminoethane were added while stirring under N₂ atmosphere. The reaction mixture was stirred for 72 hours at RT. The reaction mixture was filtered and the resin was washed with 20 ml of dry CH₂Cl₂, 20 ml of methanol. The solid resin was discarded. The organic solvent was removed by vacuum. The solid residue was further purified by flash column chromatography (SiO₂, CHCl₃/MeOH, 95:5) to afford white solid of YL-105.

Further purification was performed by preparative HPLC. Molecular weight was determined by MS.

Example 5 Synthesis of (N-2-hydroxylethyl-Aib-DTrp-DPro-diisobutylamide (YL-185) (Reductive Alkylation)

1 mmol of YL-156 (αAibDTrpDPro-diisobutylamide) was dissolved in 40 ml dry methanol in a 100 ml round-bottom flask and 1.5 mmol of NaBH₄ in THF was added while stirring under N₂ atmosphere. The solution was acidified by adding trifluoracetic acid in methanol to adjust the pH to 6.5. Then 1.15 mmol of ethylaldehyde was added in 10 ml dry methanol and the reaction mixture was stirred for 16 hours at RT. The solvent was removed by vacuum. The remaining residue was dissolved in 30 ml CH₂Cl₂ and washed with 20 ml of saturated aqueous NaHCO₃. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Further purification was done by flash column chromatography (SiO₂, CHCl₃/MeOH, 95:5) to afford white solid of YL-185.

Further purification was performed by preparative HPLC. The molecular weight was determined by MS.

Example 6 Synthesis of (N-isobutyl)Aib-DTrp-DPro-diisobutylamide (YL-194) (Hoffman Alkylation)

1 mmol of YL-156 (αAibDTrpDPro-diisobutylamide) was dissolved in 40 ml dry CH₂Cl₂ in a 100 ml round-bottom flask. 2 mmol of K₂CO₃ was then added while stirring under N₂ atmosphere. 1.15 mmol of 1-bromo-2-methylpropane was added in 10 ml dry CH₂Cl₂ and the reaction mixture stirred for 72 hours at RT. The reaction mixture was washed with 20 ml of saturated aqueous NaHCO₃ and 20 ml of saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Further purification was done by flash column chromatography (SiO₂, CHCl₃/MeOH, 95:5) to afford white solid of YL-194.

Further purification was performed by preparative HPLC. Molecular weight was determined by MS.

Example 7 Synthesis of Aib-DTrp-DTrp-Phe-Arg-5-aminopentylamide CL-174)

0.7 mmol of Fmoc-Aib-DTrp-DTrp-Phe-ArgCOOH was synthesized by Research Genetics Laboratory by the solid phase method and added to a 100 ml round-bottom flask with 40 ml of dry CH₂Cl₂. 0.70 mmol of 1-hydroxybenzotriazole was added while stirring under N₂ atmosphere in an ice-bath and subsequently 0.75 mmol of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide HCl was added in 15 ml dry CH₂Cl₂ at a fast drop rate. The reaction mixture was stirred for 1 hour at 0° C. 10 mmol of 1,5-diaminopentane in 20 ml of CH₂Cl₂ was added quickly and stirring was continued for an additional 18 h at ambient temperature. The reaction mixture was washed with 20 ml of saturated NaHCO₃ aqueous solution and 10 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Further purification was done by flash column chromatography (CHCl₃/MeOH, 95:5) to afford white solid of Fmoc-Aib-DTrp-DTrp-Phen-ArgCONH(CH₂)₅NH₂. This compound was dissolved in 20 ml of CH₂Cl₂ and under N₂ atmosphere 10 ml of piperidine was added. The solution was stirred for another 4 hours. The solvent was removed by vacuum and the residue was further purified by flash column chromatography (CHCl₃/MeOH, 95:5) to afford white solid of YL-174.

Further purification was performed by preparative HPLC. Molecular weight was determined by MS.

Example 8 Synthesis of Aib-DTrp-DPro-3-methylpiperidinamide (YL-111)

(Aib-DTrp-DPro-R, R=various of amine end groups, for example piperidine, 3-methyl piperidine, etc. All other Aib-DTrp-DPro-R compounds can be synthesized by using the same procedure):

(1) Synthesis of DPro-3-methylpiperidinamide (methylpiperidine) (1):

1 mmol of Boc-DPro (Boc=tert-Butoxycarbonyl group) was dissolved in 30 ml dry CH₂Cl₂ in a 100 ml round-bottom flask, 1 mmol of 1-hydroxybenzotriozole added while stirring under N₂ atmosphere in an ice-bath, 1.05 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodimide HCL was added in 10 ml dry CH₂Cl₂ at a fast drop rate and the reaction mixture stirred for 1 hour at 0° C. 1.1 mmol of 3-methylpiperazine in 10 ml of CH₂Cl₂ was added dropwise and stirring was continued for an additional 18 h at ambient temperature. The reaction mixture was washed with 30 ml of 20% aqueous citric acid, 30 ml of saturated aqueous NaHCO₃, and 30 ml of saturated aqueous sodium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. Further purification was done by flash column chromatography (SiO₂, CHCl₃/MeOH, 95:5) to afford white solid of Boc-DPro-D-piperidinamide.

Under N₂ atmosphere, the Boc-DPro-3-piperidinamide was dissolved in ml of CH₂Cl₂ and 10 ml of trifluoracetic acid added while stirring. The reaction mixture was stirred for 30 min. All volatiles were removed under vacuum and the residue dissolved in 30 ml of CH₂Cl₂ and washed with 10 ml saturated NaHCO₃ aqueous solution. The organic layer was removed and the aqueous layer extracted with CH₂Cl₂ (3×10 ml). The organic layer was dried over anhydrous sodium sulfate and filtered and the solvent was removed by vacuum. The residue was further purified by column chromatography (SiO₂, CHCl₃/MeOH, 85:15) to afford 0.65 mmol (65%) of compound (1) which was characterized by TLC and mass spectra, M⁺=196.3.

(2) Synthesis of DTrp-DPro-3-methylpiperidinamide (methylpiperidine) (2):

In a 100 ml round-bottom flask, 0.63 mmol of Boc-DTrp was dissolved in ml dry CH₂Cl₂ 0.66 mmol of 1-hydroxybenzotrizole was added while stirring under N2 atmosphere in an ice-bath. 0.63 mmol of 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide HCL was added in 10 ml dry CH₂Cl₂ at a fast drop rate and the reaction mixture was washed with 20 ml of 20% citric acid aqueous solution, 20 ml of saturated NaHCO₃ aqueous solution and 20 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Further purification was done by flash column chromatography (CHCl₃/MeOH, 95:5) to afford white solid of Boc-DTrp-DPro-3-piperidinamide.

Under N₂ atmosphere, the Boc-DTrp-DPro-3-piperidinamide was dissolved in 25 ml of CH₂Cl₂ and 10 ml of trifluoracetic was added while being stirred. The reaction mixture was stirred for 30 min. All volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH₂Cl₂ and washed with 10 ml saturated NaHCO₃ aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH₂Cl₂ (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuum. The residue was further purified by column chromatography (SiO₂, CHCl₃/MeOH, 85:15) to afford 0.43 mmol (68.3%) of compound (2) which was characterized by TLC and mass spectra, M⁺=382.46.

(3) Synthesis of Aib-DTrp-DPro-3-methylpiperidinamide (methylpiperidine) CL-111):

In a 50 ml round bottom flask, 0.33 mmol of Boc-Aib was dissolved in 20 ml dry CH₂Cl₂ and then 0.31 mmol of 1-hydroxybenzotriazole was added while stirring under N₂ atmosphere in an ice-bath. 0.35 mmol of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide HCL was added in 10 ml dry CH₂Cl₂ at a fast drop rate and the reaction mixture was stirred for 1 hour at 0° C. 0.30 mmol of (2) in 15 ml of CH₂Cl₂ was added dropwise and stirring was continued for an additional 18 h at ambient temperature. The reaction mixture was washed with ml of 20% citric acid aqueous solution, 20 ml of saturated NaHCO₃ aqueous solution and 20 ml of saturated sodium chloride aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum. Further purification was done by flash column chromatography (CHCl₃/MeOH, 95:5) to afford white solid of Boc-Aib-DTrp-DPro-3-piperidinamide.

Under N₂ atmosphere, the Boc-Aib-DTrp-DPro-3-piperidinamide was dissolved in 25 ml of CH₂Cl₂ and 10 ml of trifluoracetic acid was added while being stirred. The reaction mixture was stirred for 30 min. Al volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH₂Cl₂ and washed with 10 ml saturated NaCHO₃ aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH₂Cl₂ (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuum. The residue was further purified by column chromatography (SiO₂, CHCl₃/MeOH, 85:15) to afford 0.28 mmol (84.8%) of compound (YL-111) which was characterized by TLC and mass spectra M⁺=468.6.

Biological Activity

In vitro and in vivo activity of certain compounds were determined in rats and adult beagle dogs (in vivo activity only). The results are described in Tables 3, 4, 5, 6 and 7 below.

The GHRP-2 (reference standard) has the structure DAla-DβNal-Ala-Trp-DPhe-Lys-NH₂ (Chen and Clarke, J. Neuroend. 7: 179 (1995)).

TABLE 3 In Vitro Release of Growth Hormone in Rat Compound GH R¹-N-Aib ng/ DTrpX* GHRP-2 ml Where X is: control .001 .0001 .0003 .001 .003 .01 .03 .1 .3 1 DPro NH₂ 752 1525 922 1102 997 1250 1535 1550 1716 DPro-diiso- 523 1307 1322 1529 1427 1155 1124 butylamide R¹-N-2- 341 1427 — — 452 326 526 820 1163 1217 Ohethyl DPro-diiso- butylamide R¹-N₂N-di-2- 341 1427 — — 433 395 446 592 905 1206 OHethyl/ DPro diiso- butylamide R¹-N- 510 1413 — — 523 461 779 742 1079 1292 ethyl/DPro diisobutyl- amide R¹-Nentyl/ 341 1427 — — 570 698 982 1307 1467 1387 DPro diisobutyl- amide DPro- 543 1065 554 578 554 630 823 908 925 dipropyl- amide DPro- 523 1307 512 647 833 995 1253 1612 butylamide DPro- 622 1290 569 830 1172 1184 1335 1451 pentylamide DPro- 523 1307 1348 1561 1287 1021 1451 dipentyl- amide DPro- 389 821 529 553 721 728 886 978 piperidine-3- methylbenzyl ether N,N- 397 593 418 395 489 536 642 diethylnipe- cotamide -N-piperazine 553 1167 672 675 856 1049 methyl- sulfonamide DPro- 389 821 375 368 481 587 802 912 diethylamide DPro-m- 308 1052 434 458 633 837 968 methylpiper- idine DPro-3,3- 466 1126 926 1118 1169 1177 1283 diphenyl- propylamide DPro-4- 376 1125 419 451 540 808 piperidino- piperidin- amide DPro-4- 455 1520 624 777 1034 1186 1533 1772 phenylpiper- idinamide DPro-N- 389 821 467 532 573 605 816 909 methyl- piperiazine DPro-2- 397 593 394 413 433 485 548 morpholino- ethylamine DPro- 385 915 440 512 691 819 956 922 1057 spiroindole methyl- sulfonamide DPro- 614 1288 714 873 1149 1241 pyrrolidine amide DPro- 486 1344 836 1127 1283 1235 1258 1220 1327 indoline amide DPro-3- 486 1344 1008 1199 1209 1348 1626 1567 piperidine methanol amide DPro-tropin 510 1220 542 797 1001 1124 1234 amide DTrpPhe- 752 1525 1228 1416 1712 1648 1621 Arg-5-amino pentamide *Unless otherwise stated, R¹ is H

TABLE 4 In Vivo Release of Growth Hormone in Rat Compound R¹-N₂-AibDTrpX* GHRP-2 GH ng/ml Where X is: control .1 .1 .3 1 3 10 30 100 DPro NH₂ 223 1580 326 433 1159 2217 3155 DPro- 111 1066 642 1524 1837 2307 2913 diisobutylamide R¹ = -N-2-OHethyl/ 92 2051 — — — 156 259 451 — DPro-diiso- butylamide R¹ = N,N-di-2- 96 799 — — — 124 208 543 OHethyl/ DPro-diiso- butylamide R¹ = N-ethyl/ 92 2051 — — 189 177 268 374 — DPro-diiso- butylamide R¹ = -N-pentyl/ 92 2051 — — 124 398 371 789 — DPro-diiso- butylamide DPro-dipropylamide 91 1082 92 220 305 579 1646 2089 DPro-butylamide 111 1066 196 329 647 2005 1596 DPro-pentylamide 170 1289 310 581 820 1660 2280 DPro-dipentylamide 128 1071 87 182 322 355 632 482 1206 DPro-piperidine-3- 150 1235 669 1725 2319 methyl-benzyl ether N,N-diethylnipecot- 117 579 221 928 2070 2896 2186 amide -N-piperazine 113 942 241 933 1965 1997 methyl-sulfonamide DPro-diethylamide 128 919 448 766 1719 2465 3088 DPro-m- 93 445 832 1557 1570 1762 methylpiperidine DPro-3,3-diphenyl- 114 1106 141 147 138 249 383 624 propylamide DPro-4-piperidino- 150 1235 378 1318 2403 piperidin-amide DPro-4- 111 568 112 238 499 phenylpiperidin- amide DPro-N-methyl- 128 919 218 425 1974 2314 piperazine DPro-2-morpholino- 111 568 900 1585 2195 ethylamine DPro-spirouidole 120 586 192 485 861 1177 methyl-sulfonamide DPro-pyrrolidine 98 1227 1024 2116 2381 amide DPro-indoline amide 69 1279 142 317 269 885 DPro-3-piperidine 91 1082 155 668 1483 2616 2711 methanol amide DPro-tropin amide 73 1814 114 87 183 362 383 769 DTrpPhe-Arg-5- 109 1718 262 274 2272 2929 amino pentamide 8 0 *Unless otherwise stated, R¹ is H

TABLE 5 In Vivo Release of Growth Hormone in Adult Beagle Dogs Compound oral Time R¹-N₂-AibDTrpX* dose (hr) Where X is: (mg/kg) 0 0.5 1 2 3 4 5 6 7 8 DPro NH₂ 4 0.7 38 14 9 5 13 7.1 3.3 4 2.5 1.3 4 0.8 54 30 15 12 4.8 4.2 3.4 1 0 8 DPo- 4 0.8 27 9.4 14 22 22 21 11 6.9 5.4 diisobutylamide 4 1.4 141 50 74 15 7.5 4 4.4 5 7 2.3 2 0 6 54 30 22 15 7 4.6 4.8 2 7 1.8 1 2.6 85 30 16 7.7 6 0.9 2.5 2.5 1 6 1 <0.5 128 50 24 24 5.6 6.1 2.9 2.2 — 1 1.5 89 59 30 11 7 6.2 5.2 3.7 3.2 R¹ = -N-2-OHethyl/ 1 3.8 102 26 25 10 6.1 5.6 4.0 5.2 5.0 DPro-diisobutyl- 1 1 62 30 19 5 6 3.8 2.0 2.5 2.0 1.6 amide 1 R¹ = -N₂N-di-2- 1 OHethyl/DPro- diisobutylamide R¹ = -N-ethyl/ 4 1.3 100 29 20 9.4 3.9 2.2 2.4 1.5 5.6 DPro-diisobutyl- 1 1 1 17 4.4 1 2 1.5 1.4 1.1 1.2 1 4 1.2 amide R¹ = -N-pentyl/ 1 DPro-diisobutyl- amide DPro-dipropylamide 4 3.2 112 52 29 25 13 6.1 3.6 2.9 2.5 1 0.6 27 19 5 6 1.6 1.6 0.6 1.4 0.8 0.8 DPro-butylamide 4 1.1 92 43 26 53 14 5.4 3.5 3.9 1.3 2 1.8 60 40 13 3.8 3.7 2.2 2.6 2.4 1.7 DPro-pentylamide 4 1 72 12 11 6 4.9 3.5 2.5 1.9 1.4 DPro-dipentylamide 4 2.3 53 20 1.3 15 15 8.9 9.2 6.6 4 3 4 3.7 32 11 8.4 7.2 3.6 3.5 2.3 2.7 <0.1 4 2.9 11 11 15 3 3.3 2.5 2.7 2.3 2 DPro-piperidine-3- 4 2 >12 59 63 28 11 6.7 4.2 4.1 1.8 methyl-benzyl ether 4 0.8 8 28 27 11 14 14 11 4.7 6.8 2 3.2 127 42 63 45 13 5.5 4.5 3.4 3.2 2 3.6 169 39 23 6.3 4.5 1.7 2.7 2.3 1.9 F0.5iv 2.9 112 78 27 9.3 4.5 4.1 2.9 4.1 4.1 81 N,N-diethylnipe- 4 1.7 57 13 5 3 5 5 3.4 3.1 1.9 2 1.7 cotamide 4 0.9 43 8 2 2 1 0.8 0 9 2.1 6 9 0.9 4F 2.7 6 3 7 3 3.7 2 2 0.9 10 3 6 3 5 3.5 3 5 1 -N-piperazine 4 2 1 57 12. 8.7 3.8 1.7 2.2 1.6 6.3 3.2 methyl-sulfonamide 5 DPro-diethylamide 4 2.4 56 38 29 28 16 9.1 6.2 3.9 2 8 4 1.7 134 89 105 86 16 7.1 5.1 4.5 3 2 F0 5iv 1 6 60 18 6 3 7 2.5 2 1.9 1.7 2.5 DPro-m- 4 1 54 — 50 52 20 27 8 1 9 6 1.7 methylpiperidine 4F 1.4 72 84 18 4.7 3.5 1.4 1 1 1 6 1 5 4 2.1 118 55 54 53 34 13 11 11 6.4 2 1 2 128 59 29 12 8.9 3 6 3 3 1 7 1 1 6 53 19 15 9.6 3.1 2.2 1 5 2.2 1 1 2 63 32 17 13 12 1.5 2.4 3 2 2 DPro-3,3-diphenyl- 4 1.6 119 54 17 16 10 5.6 4.2 3.3 2.7 propylamide 4 2.2 54 12 8.6 7 4 13 5.9 3.4 3 ns DPro-N-methyl-1- 4 1 100 22 83 7.9 4 8 2 6 2 9 2.3 1.8 piperazine 0.5iv 0.8 41 31 7 3.3 2 6 1 5 2.4 0.9 1.1 DPro-spiroundole 4 1.5 <0. 5.5 1.6 1.5 2 2 4.7 1.7 1.6 0.9 methyl-sulfonamide 5 DPro-pyrrolidine 4 2 3 104 28 18 7.1 5.1 3 2 2.7 2.2 2.3 amide 4 2.1 63 32 45 30 11 6 4.9 4 1 3.6 DPro-indole amide 4 1.2 7 7.5 5.8 4.7 3.1 2.8 2.5 2 1.6 DPro-3-piperidine 4 2.3 55 14 7.5 2.9 3.8 3.4 2 4 2.3 1.8 methanol amide DPro-tropinamide 4 1.9 72 47 5.5 3.8 3.8 2.8 2.5 2.2 2.2 DTrpPhe-Arg-5- 2 3.1 83 20 6.8 3.9 2.9 3.3 3.1 3.3 3 amino pentamide 1 2.5 38 8.5 2.8 2.3 1.4 1.7 2.1 2 0.8 *Unless otherwise stated, R¹ is H

TABLE 6 In Vivo * Release of GH Rat GHRP-2 GH ng/ml # Compound iv control .1 .01 .03 .1 .3 1 3 10 30 861 inipDαNalDTrpNH₂ 145 1251 485 2197 2380 1473 inipDαNalDValNH₂ 145 1251 225 225 1466 αAibDTrpDValNH₂ 145 1251 124 418 1415 αAibDTrpDProDSerNH₂ 120 1465 820 1658 2306 2896 1417 αAibDTrpDProDArgNH₂ 120 1465 1362 2161 2057 1246 αAibDTrpDProDPheNH₂ 92 566 203 594 1901 2339 1248 αAibDTrpDProDTrpNH₂ 145 1343 229 1814 1460 αAibDTrpDValDValNH₂ 145 1343 104 240 1461 αAibDValDProDValNH₂ 145 1343 160 261 1464 αAibDValDValDValNH₂ 145 1343 96 197 1468 αAibDTrpDProDLysNH₂ 145 1343 157 791 1462 αAibDProDProDValNH₂ 145 1251 218 185 1472 inipDαNalDTrpDValNH₂ 145 1251 174 142 154 1019 1489 αAibDTrpDProIleNH₂ 135 1734 445 355 1884 1476 αγAbuDαNalDTrpDIleNH₂ 166 1175 97 111 152 152 1495 inipDαNalDTrpDProIleNH₂ 166 1175 824 1971 1496 inipDαNalDTrpPheIleNH₂ 166 1175 1638 2055 1471 inipDαNalDTrpDValArgNH₂ 145 1251 98 184 843 1469 αAibDTrpDProDValDValNH₂ 164 411 783 2450 1975 1480 αAibDTrpDProDProDPalNH₂ 78 990 245 622 2775 1481 αAibDTrpDProDValArgDProNH₂ 164 411 1703 2145 2278 2511 1484 αAibDTrpDProDIleDArgNH₂ 105 750 317 562 1863 2224 2446 1475 αγAbuDTrpDTrpDIleNH₂ 101 369 123 125 113 1486 inipDαNalDTrpPheDValNH₂ 101 369 203 352 1009 1488 αAibDTrpDProValNH₂ 105 750 323 644 1725 1465 αAibDTrpDIleDIleNH₂ 105 750 160 1500 αAibDTrpDProLeuNH₂ 225 1429 1831 2623 1492 αAibDTrpDProThrNH₂ 164 411 125 176 1031 1497 DHisDTrpDProDValArgNH₂ 164 411 154 181 235 601 1451 DHisDTrpDProDThrNH₂ 128 811 1380 2450 3133 2731 (.03) 135 1734 898 1452 αAibDTrpDProDIleNH₂ 105 750 1028 1837 2138 1474 αAibDTrpDPheDValNH₂ 101 369 146 117 184 1478 αAibDTrpDProDValDArgNH₂ 124 1251 1420 2304 2245 135 1734 1177 1293 αAibDTrpDProDAlaNH₂ 157 1171 416 341 1682 3295 1226 αAibDTrpDProDProNH₂ 124 1072 2129 1136 αAibDTrpDProArgNH₂ 120 1465 297 670 1769 2644 1251 αAibDTrpDProDValNH₂ 188 439 228 832 1581 2405 120 1465 1584 2360 2181 3250 1325 inipDαNalDTrpDProNH₂ 120 1465 409 1203 2475 1518 αAibDαNalDProDValDArgNH₂ 99 1179 298 722 1695 2279 1520 αAibDαNalDProDIleDArgNH₂ 99 1179 325 640 1481 2497 1487 αAibDTrpDProDProDLysNH₂ 135 1734 171 676 1562 1506 αAibHisDβNalDPheLysNH₂ 136 1169 137 244 1416 1507 αAibHisDTrpDProDValNH₂ 136 1169 129 94 118 1508 αAibHisDTrpDProDIleNH₂ 136 1169 132 137 123 1509 αAibHisDTrpDProValArgNH₂ 136 1169 157 138 123 1510 αAibHisDTrpDProDValArgNH₂ 136 1169 145 133 246 1511 αAibDβNalDProDValNH₂ 136 1169 171 246 286 1512 αAibDαNalDProDValNH₂ 136 1169 143 141 611 1523 αAibDTrpDProDThrArgNH₂ 99 1179 1336 2219 2167 2781 1524 αAibDTrpDProDNleArgNH₂ 99 1179 1425 1952 2334 2164 17 1395 298 1151 2593 2275 2672 1525 αAibDTrpDProDNValArgNH₂ 99 1179 1397 2061 2285 2250 117 1395 146 580 1380 2047 1853 1490 αAibDTrpDProIleArgNH₂ 135 1734 173 202 179 105 750 137 397 1479 αAibDTrpDProDProArgNH₂ 101 369 2081 2566 2269 1493 αAibDTrpDProProArgNH₂ 225 1429 96 152 431 1483 αAibDTrpDProDProDArgNH₂ 135 1734 333 1838 1485 αAibDTrpDProDIleArgNH₂ 78 990 969 1472 1981 2073 3289 1407 αAibDTrpDProPheDSerNH₂ 138 1004 389 1365 1137 αAibDTrpDProPheArgNH₂ 120 1465 225 175 149 1470 αAibDTrpDProDValArgNH₂ 145 1251 600 1576 2647 2002 3414 803 SarDTrpDTrpPheArgNH₂ 120 1465 778 1894 2498 1532 αAibDαNalDProDProArgNH₂ 124 1012 1989 1533 αAibDαNalDProDNValArgNH₂ 124 1012 1910 1519 αAibDαNalDProDIleArgNH₂ 99 179 1641 1491 2354 2370 1521 αAibDαNalDProDValLysNH₂ 99 179 573 1372 2008 2355 1530 αAibDαNalDProDThrArgNH₂ 124 1012 388 317 1035 2873 2611 1531 αAibDβNalDProDThrArgNH₂ 124 1012 2303 1513 αAibDβNalDProDValArgNH₂ 136 1169 611 3230 3322 1514 αAibDαNalDProDValArgNH₂ 136 1169 1508 2710 2562 117 1395 404 687 1624 2516 2507 1534 αAibDTrpDProDNleNH₂ 120 1132 436 718 1968 1535 αAibDTrpDProDNValNH₂ 120 1132 228 614 1710 αAibDTrpDProDIle-X TJ 39 2-aminoethylamide 124 1012 1416 1739 2742 2931 TJ 49 5-aminopentylamide 120 1132 1262 2822 2501 2426 TJ 53 3-aminopropylamide 120 1132 575 1697 2603 1901 αAibDTrpDProDVal-X TJ 45 2-aminoethylamide 117 1395 813 1958 1736 TJ 6 dimethylamide 135 1734 247 836 1362 1805 TJ 8 diethylamide 135 1734 232 255 366 1157 αAibDTrpDProDPro-X TJ 28 2-aminoethylamide 73 766 151 339 558 920 1999 353 DβNalAlaTrpDPheLysGlnGlyNH₂ 90 1542 879 1307 1268 2729 359 DAlaDTrpAlaTrpDPheLysValGlyNH₂ 151 2553 3653 2530 90 1542 452 1763 3364 3003 371 DAlaDβNalAlaTrpDPheLysGlnGlyGlyGlyNH₂ 157 983 535 1834 2176 2116 3995 356 DAlaDTrpAlaTrpDPheLysHisGlyNH₂ 90 1542 1252 2811 1886

TABLE 7 In Vivo* Release of GH in Adult Beagle Dogs oral Time (hr) dose 0 0.5 1 2 3 4 5 6 7 8 # Compound mg/kg Canine GH ng/ml αAibDTrpDProDIleX TJ49 5-aminopentylamide 1 5.4 123 27 21 20 5.6 2.3 1.2 0.8 1.4 1 3.8 116 20 5.7 13 19 3.3 1.1 1 1.1 TJ53 3-aminopropylamide 1 6 44 19 22 7.8 6.4 6.7 5.4 6.4 6.9 1 5.9 91 32 19 7.3 6.2 13. 6.6 4.7 5.6 2 TJ39 2-aminoethylamide 1 5.7 31 11 10 10 4 4.4 3.8 5.1 3.4 1 3.4 99 21 19 14 9.1 4.6 4 4.2 3.8 TJ66 4-aminobutylamide 1 1.8 100 20 19 4 2.8 2.7 2.1 3.4 2.8 αAibDTrpDProDValX TJ6 N-dimethylamide 1 5.1 9.5 5.4 5.6 5.5 6 6.2 5 6.4 3.8 TJ8 N-diethylamide 1 20 8.7 5 15 6 4.4 4.8 5.1 4.3 4.4 TJ45 2-aminoethylamide 1 6.4 97 26 24 8 3 6 12 9 8 1 7.6 52 24 21 13 9 8 9 8 8 αAibDTrpDProDValX TJ61 5-aminopentylamide 1 3.7 41 12 5.3 4.4 4.1 3.7 3.5 4.8 4.1 1 2.3 91 17 26 7.6 4.2 3.5 3 3.8 2.7 αAibDTrpDProDNleX TJ59 5-aminopentylamide 1 6.4 54 16 13 5 5 5.1 6.9 6.4 5.9 1 6.7 112 19 14 13 7.4 6.6 7.1 6.4 5.4 1476 αAibDTrpDProDValDArgNH₂ 2 3.2 42 31 13 25 5 3.1 4.1 2.6 1.7 1513 αAibDβNalDProDValArgNH₂ 1 6.6 128 38 47 35 25 8.7 6.5 6.9 7.2 1 5.3 125 22 8.7 6.3 5 3.6 3.6 6.7 3.6 1514 αAibDαNalDProDValArgNH₂ 1 3.5 31 10 5.8 5.4 4.2 3.2 3.8 3.4 3.6 1 3.5 126 24 31 14 7.3 3.5 4.8 3.1 4.9 1519 αAibDαNalDProDIleArgNH₂ 1 6.8 72 28 21 13 6.5 5.5 4.4 6.9 5.2 1521 αAibDαNalDProDValLysNH₂ 1 3.7 111 39 61 29 14 8.2 4 4.4 4.7 973 inipDαNalDβNalPheArgNH₂ 2 3.1 13 4.2 3.3 2.5 2.1 2.9 2.3 2.9 2.4 1536 αAibDTrpDProDIleArgGlyNH₂ 0.5 1.5 93 23 29 8.2 6.5 5.5 4.3 4.3 2.9 1537 αAibDTprDProDNleArgGlyNH₂ 0.5 3.7 76 12 10 2.6 3.1 2.3 2.3 2.8 2.8 1539 αAibDTrpDProDThrArgGlyNH₂ 0.5 1.8 86 28 85 13 7.6 4.8 2.7 2.7 2.3 1252 αAibDTrpDProDGlnNH₂ 2 1.5 2.6 6.4 3.5 2.8 2.5 2.3 1.9 1.9 2 869 InipDαNalDTrpPheCOOH 2 2.6 3.5 2 2.6 2.7 2.6 2.5 3.6 3.6 3.2 1 1.4 1.8 1.3 1.5 1.3 2.1 1.9 2.6 1.4 2.1 956 InipDαNalDTrpValNH₂ 1 4.2 3.3 3.9 4 3.6 5.5 3.4 3.8 2.3 3.1 1136 αAibDTrpDProArgNH₂ 1.1 4.9 15 8.3 6.3 4.8 5.2 4.8 4.3 5.1 4.8 1 1.7 27 8.7 1.5 1.9 1.9 2.4 2.7 1.6 2.7 1118 αAibDTrpDProCHαAlaNH₂ 1 6.6 3.8 2.6 2.6 2.8 2.8 1.9 2.1 2.9 2.6 1251 αAibDTrpDProDValNH₂ 2 2.9 47 16 14 7.8 5.6 4.7 5.6 6.8 4.9 2 1.6 28 5.6 4.1 4.1 4 4.1 4.2 3 2.6 1.1 2.4 128 31 42 5.5 4.8 4.4 3.4 4.4 3.4 1293 αAibDTrpDProDAlaNH₂ 2 4.6 11 4.9 4.9 4.6 5.5 5.9 4 4.7 4.7 2 2.9 15 8.9 11 4 3.8 3 2.7 3.6 2.7 2 3.9 14 6.2 3.8 2.7 1.9 2.9 2.4 3.4 3.1 1452 αAibDTrpDProDIleNH₂ 2 2.5 117 23 13 4.1 3.6 5 4.3 5.2 4.7 1451 αAibDTrpDProDThrNH₂ 2 1.4 20 4 3.9 2.7 2 1.7 2.5 2.6 1.6 1.6 3.3 51 22 58 7.1 5.6 4.9 4.6 4.6 4.1 1246 αAibDTrpDProDPheNH₂ 2 1.7 29 20 9.2 3.7 2.7 1.6 1.9 2.4 1.8 1474 αAibDTrpDPheDValNH₂ 2 3.2 2.9 2.8 2.7 2.9 2.9 2.8 2.8 4.7 2.7 1248 αAibDTrpDProDTrpNH₂ 2 1.8 5.9 2.7 1.4 2.2 1.8 1.7 1.3 3.2 3.3 1479 αAibDTrpDProDProArgNH₂ 1.8 2 38 9.3 6.2 6.1 6 5.7 4.7 2.7 2.1 1478 αAibDTrpDProDValDArgNH₂ 2 3.2 42 31 13 25 5 3.1 4.1 2.6 1.7 1470 αAibDTrpDProDValArgNH₂ 2 3.6 62 26 30 30 6.8 13 14 6.5 5.4 2 3.4 37 32 41 13 23 9.2 8 4.9 4.1 1 5.1 32 14 18 16 14 11 6.3 6.3 5.2 1485 αAibDTrpDProDIleArgNH₂ 2 4.9 102 19 48 23 11 8 9 16 21 2 5.7 49 38 26 10 21 7.6 6.7 10 11 2 3.5 20 17 15 16 18 13 19 13 14 2 1.2 60 34 15 9.2 5.3 4.5 4.7 1 4.6 136 23 95 14 22 8.3 6.9 4.9 5.2 1 6.7 104 47 84 41 29 15 19 15 5.4 1 5.2 50 17 11 6.9 6.8 6.2 7.1 6.7 4.5 0.5 6 110 63 32 13 12 4.9 5 5.6 5.4 0.5 7.8 109 78 54 49 97 52 51 22 16 0.5 6.1 126 78 32 12 7.8 4.3 15 9.2 3.6 0.5 6.6 125 57 35 20 11 40 15 8 8 0.5 5.9 227 28 26 40 13 50 9 7 7 0.25 3.5 102 35 32 28 5.8 3.7 4.1 5 6.9 0.25 2.1 53 13 10 3.1 2.1 4 3.3 4.4 0.125 3.6 48 23 7.9 3.8 3 3.9 3 5.7 3.4 0.125 2.6 53 16 7.6 3.3 3.9 3.9 3.6 5.3 3.2 1523 αAibDTrpDProDThrArgNH₂ 1 5.4 105 63 40 30 15 8 9.3 7.9 4 1524 αAibDTrpDProDNleArgNH₂ 1 5.3 110 105 128 38 25 18 7.8 4.5 3.8 0.5 5.6 72 23 10 7.1 7.1 6.7 6.4 5.9 5.6 1525 αAibDTrpDProDNValArgNH₂ 0.5 6 99 58 26 13 7.8 6.2 6 5.7 4.6 TJ64 5-aminopentylamide 1 1.5 32 13 5.6 3.5 2.3 2.7 1.4 2.9 3.2 

1. A method of promoting the release and elevation of blood growth hormone levels by administering a compound having the formula A_(1″)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl) amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl) amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z, wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R₁-R₂-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof in an effective amount with a second compound, wherein the second compound is a compound which acts as an agonist at the growth hormone releasing hormone receptor or inhibits the release of somatostatin.
 2. A method of promoting the release and elevation of blood growth hormone levels by administering a compound having the formula A_(1″)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A₂- or A₂-; wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl) amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z, wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof; with at least one of (1) a naturally occurring growth hormone releasing hormone, (2) a functional equivalent thereof, or (3) a compound which promotes the release of growth hormone.
 3. A method for treating hypothalamic pituitary dwarfism, osteoporosis or burns, which comprises administering a therapeutically effective amount of a compound having the formula A_(1′)-Y, wherein A₁- is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers. DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl) amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH: (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromalic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers DαNal or DβNal; and R₂ is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8 or pharmaceutically acceptable salts thereof.
 4. A method for promoting wound healing, promoting recovery from surgery or recovery from acute/chronic debilitating illnesses which comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a compound having the formula A_(1′)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A₂-; wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl) amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A₁′ is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R₁-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₂ is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable carrier or diluent.
 5. A method for reduction of cachexia in cancer patients which comprises providing a therapeutically effective amount of a compound having the formula A_(1′)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z, wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₂ is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 6. A method for promoting anabolism and/or to decrease catabolism in humans which comprises administering a therapeutically effective amount of a compound having the formula A_(1′)-Y, wherein A_(1″)is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z, wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, burylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically aceeptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 7. The method of claim 6, wherein the therapeutically effective amount is about 30 μg to 1200 μg of the compound per kg of body weight.
 8. A method for increasing muscle in an animal which comprises administering an effective amount of a compound having the formula A_(1′)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A₂-; wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, penlylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 9. A method for improving serum lipid pattern in humans by decreasing in the serum the amount of serum cholesterol and low density lipoprotein and increasing in the serum the amount of the high density lipoprotein which comprises administering an effective amount of a compound having the formula A_(1″)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamnide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂, or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1)R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or βNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 10. A method for decreasing atherosclerosis which comprises administering an effective amount of a compound having the formula A_(1″)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CHx is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 11. A method to improve cardiac performance in congestive heart failure and in patients with cardiac myopathy which comprises administering an effective amount of a compound having the formula A_(1′)-Y, wherein A_(1′) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″) or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CHx is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 12. A method to improve sleep which comprises administering an effective amount of a compound having the formula A_(1′)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″)- or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CHx is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof.
 13. A method of promoting the release and elevation of blood growth hormone levels by administering a compound having the formula A_(1″)-Y, wherein A_(1″) is Aib, inip, ABU, βAla, His, Sar or any of their respective D-isomers; Y is A_(2′)-A₃-A₄-A₅-A₆-Z′; A_(2′)-A₃-A₄-A₅-Z′ or A_(2′)-A₃-A₄-Z′; wherein A_(2′) is A₅-A_(2″)- or A_(2″); wherein A₅ is a spacer amino acid; A_(2″) is any natural L-amino acid, Pal, or their respective D-isomers, DαNal or DβNal; A₃, A₄ and A₅ are any natural L-amino acid, Pal, αNal, βNal, Nle, Arg-DPro, DPCl, D or L cyclohexyl-amino acid, or any of their respective D-isomers; and Z′ is NH₂, OH, C₁-C₁₀ alkylamino, di(C₁-C₁₀ alkyl)amino, amino-C₁-C₁₀ alkylamino or di(amino C₁-C₁₀ alkyl)amino; or pharmaceutically acceptable salts thereof; or a compound having the formula A₁-A₂-X, wherein A₁ is Aib, inip or ABU; A₂ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and X is (1) R₁-R₂-Z, wherein R₁ and R₂ are any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, where CH_(x) is cyclohexyl, CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; (2) DpR₃Phe-R₄-Z wherein R₃ is a halogen; R₄ is L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; (3) NH(CH₂)_(n)NH, where n is 1 to 8; (4) R₅-R₆, wherein R₅ is any natural L-amino acid, Pal, αNal, βNal, DpCl, CHx, or any of their respective D-isomers; and R₆ is diisobutylamide, dipropylamide, butylamide, pentylamide, dipentylamide, or C(=0)(substituted heteroalicyclic or heteroaromatic); (5) DTrp Phe ArgR₇, wherein R₇ is NH(CH₂)_(n)NH, where n is 1 to 8; or (6) R₈-R₉-R₁₀-Z, wherein R₈ is DTrp, DPro, DαNal or DβNal; R₉ is any natural L-amino acid or Pal, or their respective D-isomers; R₁₀ is any natural L-amino acid or Pal, or their respective D-isomers; and Z is CONH₂ or COOH; or pharmaceutically acceptable salts thereof; or of the formula A_(1′)-X′, wherein A_(1′) is Aib, inip, ABU, IMC, Ava, 4-IMA, βAla, Ileu, Trp, His, DpCl, CHx where CH_(x) is cyclohexyl, or any of their respective D-isomers; and X′ is (1) R_(1′)-R_(2′)-Z′, wherein R₁ is any natural L-amino acid or Pal, or their respective D-isomers DαNal or DβNal; and R2 is any natural L-amino acid, Pal, αNal, βNal, DpCl, Aib, CHx, or CHxAla, or any of their respective D-isomers; and Z is CONH₂ or COOH; or (2) R₃-R₄, wherein R₃ is any natural L-amino acid or Pal, or their respective D-isomers, DαNal or DβNal; and R₄ is NH(CH₂)_(n)NH, where n is 1 to 8; or pharmaceutically acceptable salts thereof. 